Preparation method of moguisteine intermediate 17 beta-hydroxyl-4 alpha, 5 alpha-epoxy androstane (2,3-d) isoxazole

A technology of epoxyandrostane and 3-d, which is applied in the field of preparation of Mojostein intermediate 17β-hydroxy-4α,5α-epoxyandrostano(2,3-d)isoxazole, can Solve problems such as the reduction of epoxide selectivity, and achieve the effect of high selectivity, high yield and low environmental pollution

Inactive Publication Date: 2011-09-14
TIANJIN KELUO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the Lewis acidity of MTO will also catalyze the further ring opening of the epoxidi...

Method used

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  • Preparation method of moguisteine intermediate 17 beta-hydroxyl-4 alpha, 5 alpha-epoxy androstane (2,3-d) isoxazole
  • Preparation method of moguisteine intermediate 17 beta-hydroxyl-4 alpha, 5 alpha-epoxy androstane (2,3-d) isoxazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: Preparation of 17β-hydroxyl-4α, 5α-epoxyandrostano[2,3-d]isoxazole

[0021] Add 3.13g (0.01mol) of 17β-hydroxy-4-androstano[2,3-d]isoxazole into a 100ml three-necked flask, then add 50ml of benzene, stir magnetically, and control the temperature at 0°C. Under temperature, add 22.6mg (0.1mmol) diazepam Schiff base (E)-4--(pyridine-2-amino) benzoic acid, 25mg (0.1mmol) rhenium trioxide and 2.27g (0.02mol) 30%H 2 o 2 Aqueous solution, after stirring for 6 hours, stop the reaction, add a little sodium thiosulfate to remove excess H 2 o 2 , the catalyst was removed by filtration, and the residue was recrystallized with acetone to obtain 2.75 g of 17β-hydroxy-4α,5α-epoxyandrostano[2,3-d]isoxazole after evaporating the solvent, with a yield of 85.0%.

[0022] Melting point 204~206℃;

[0023] 13 C NMR (CDCl 3 )6: 11.1 (s, _C-18), 16.8 (s, C-19), 20.8 (s, C-11), 23.5 (s, C-15), 27.9 (s, C-7), 30.0 ( s, C-6), 30.2 (s, C-16), 30.4 (s, C-10), 35.9 (s, C-1), 36.5 ...

Embodiment 2

[0024] Example 2: Preparation of 17β-hydroxyl-4α, 5α-epoxyandrostano[2,3-d]isoxazole

[0025] Add 3.13g (0.01mol) of 17β-hydroxy-4-androstano[2,3-d]isoxazole into a 100ml three-neck flask, then add 50ml of dichloromethane, stir magnetically, and control the temperature at 10°C. At this temperature, add 22.6mg (0.1mmol) diazepam Schiff base (E)-4--(pyridine-2-amino)benzoic acid, 25mg (0.1mmol) methyl rhenium trioxide and 2.27g (0.02 mol)30%H 2 o 2 Aqueous solution, after stirring for 5 hours, stop the reaction, add a little sodium thiosulfate to remove excess H 2 o 2 , the catalyst was removed by filtration, and the residue was recrystallized with acetone to obtain 2.03 g of 17β-hydroxyl-4α,5α-epoxyandrostano[2,3-d]isoxazole after evaporating the solvent, with a yield of 62.8%.

Embodiment 3

[0026] Example 3: Example 2: Preparation of 17β-hydroxyl-4α, 5α-epoxyandrostano[2,3-d]isoxazole

[0027] Add 3.13g (0.01mol) of 17β-hydroxy-4-androstano[2,3-d]isoxazole into a 100ml three-necked flask, then add 50ml of toluene, stir magnetically, and control the temperature at 0°C. Under temperature, add 45.2mg (0.2mmol) diazepam Schiff base (E)-4--(pyridine-2-amino) benzoic acid, 50mg (0.2mmol) methyl rhenium trioxide and 2.27g (0.02mol) respectively 30%H 2 o 2 Aqueous solution, after stirring for 6 hours, stop the reaction, add a little sodium thiosulfate to remove excess H 2 o 2 , the catalyst was removed by filtration, and the residue was recrystallized with acetone to obtain 2.27g of 17β-hydroxyl-4α,5α-epoxyandrostano[2,3-d]isoxazole after evaporating the solvent, with a yield of 70.3%.

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Abstract

The invention relates to a preparation method of moguisteine intermediate 17 beta-hydroxyl-4 alpha, 5 alpha-epoxy androstane (2,3-d) isoxazole, which includes the following steps: the moguisteine intermediate is obtained by oxidizing 17 beta-hydroxyl-4 androstane (2,3-d) isoxazole with epoxidation system (schiff base/MTO/H2O2) consisting of schiff base, methyltrioxorhenium and hydrogen peroxide. The prepared 17 beta-hydroxyl-4 alpha, 5 alpha-epoxy androstane (2,3-d) isoxazole is an important intermediate of a new anti-breast cancer medicine moguisteine. The preparation method overcomes the shortcomings in the prior art, and has the advantages of high epoxidation activity, high selectivity, little environmental pollution, high conversion rate and the like, thus having potential application value.

Description

technical field [0001] The invention relates to a preparation method of a Mojestine intermediate 17β-hydroxyl-4α, 5α-epoxyandrostano[2,3-d]isoxazole. Background technique [0002] Globally, breast cancer is the most common type of tumor in women. Morzelstein, a new breast cancer drug with a novel mechanism of action, is extremely effective in postmenopausal women whose hormone-selective cancer has spread outside the breast. The unique mode of action of Morziestan not only distinguishes it from other anti-estrogen drugs, but also is the pharmacological basis for its high effectiveness against breast cancer that has failed or resistant to other anti-estrogen therapies. Based on this, scientists have conducted a lot of research on it in recent years. [0003] 17β-Hydroxy-4α, 5α-epoxyandrostano[2,3-d]isoxazole, as an important intermediate of Morjstein, has a broad market prospect. GB 1123770 etc. have reported its preparation method, which is obtained by peroxyacid oxidation...

Claims

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Application Information

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IPC IPC(8): C07J71/00
Inventor 陈波王文龙李昆鹏梅淑贞靳敏
Owner TIANJIN KELUO PHARMA
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